在 KEYNOTE-062 三期临床试验中，肿瘤突变负荷与帕博利珠单抗联合或不联合化疗作为一线治疗胃癌的疗效相关。
Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study.
机构信息
Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Department of Digestive Oncology, University Hospitals Gasthuisberg and University of Leuven, Leuven, Belgium.
出版信息
Clin Cancer Res. 2022 Aug 15;28(16):3489-3498. doi: 10.1158/1078-0432.CCR-22-0121.
PURPOSE
This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062.
PATIENTS AND METHODS
In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb.
RESULTS
TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non-MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated.
CONCLUSIONS
This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.
目的
本预先设定的探索性分析评估了肿瘤突变负担（TMB）状态与 KEYNOTE-062 中一线帕博利珠单抗联合化疗与化疗相比的疗效和安全性结局之间的关系。
方法
在晚期胃癌患者中，对可评估 TMB 数据的患者，我们采用逻辑回归（ORR）和 Cox 比例风险（PFS、OS）回归模型，评估了 TMB（连续变量；平方根尺度）与临床结局（客观缓解率[ORR]、无进展生存期[PFS]和总生存期[OS]）之间的相关性。TMB 的临床实用性采用了预先设定的 10 mut/Mb 截断值进行评估。
结果
763 例患者中有 306 例（40.1%；帕博利珠单抗组 107 例，帕博利珠单抗+化疗组 100 例，化疗组 99 例）有 TMB 数据。TMB 与接受帕博利珠单抗和帕博利珠单抗联合化疗的患者的临床结局显著相关（ORR、PFS 和 OS，均 P＜0.05），但与化疗组（均 P＞0.05）无关。TMB≥10 mut/Mb 在各治疗组中的总体发生率为 16%；44%的 TMB≥10 mut/Mb 患者存在高度微卫星不稳定（MSI-H）肿瘤。在 TMB≥10 mut/Mb 的接受帕博利珠单抗治疗的患者（帕博利珠单抗单药治疗和帕博利珠单抗联合化疗）中观察到临床结局（ORR、PFS 和 OS）的改善。当分析仅限于非 MSI-H 亚组时，TMB 作为连续变量与 TMB 与临床结局之间的正相关关系，以及 TMB 截点时帕博利珠单抗（联合或不联合化疗）与化疗相比的临床获益，都减弱了。
结论
本对 KEYNOTE-062 的探索性分析提示，在晚期胃/胃食管交界腺癌患者中，TMB 与一线基于帕博利珠单抗的治疗的临床疗效相关。然而，在排除 MSI-H 肿瘤患者后，TMB 的临床实用性减弱了。
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